Patients with head and neck squamous cell carcinoma (HNSCC) often present with locally advanced disease and despite aggressive treatment, relapse remains a significant challenge. Evasion of apoptosis, a mode of regulated cell death, has been implicated in treatment resistance and poor prognosis, partly via overexpression of inhibitor of apoptosis proteins (IAPs). Thus, therapeutic strategies targeting the anti-apoptotic machinery are being explored; one such strategy is the design of compounds that mimic the naturally occurring endogenous second mitochondria-derived activator of caspases (SMAC) compound, namely SMAC mimetics. Several SMAC mimetics have shown activity in pre-clinical models of HNSCC with a range of anti-tumour effects, that appear to be time and context-dependent, including anti-proliferative signalling, apoptosis re-activation, enhanced sensitivity to radiation treatment, immunomodulation, and T-cell response potentiation. Xevinapant demonstrated promising activity in a phase I/II study in locally advanced HNSCC, in combination with standard of care radical chemoradiation, and has since been the focus of several phase II/III trials in the locally advanced and adjuvant settings. Additionally, tolinapant is being investigated in combination with definitive and adjuvant radiotherapy in locally advanced HNSCC. In this chapter, we shed light on the rationale for IAP targeting in HNSCC and provide an updated review of the existing pre-clinical data and clinical studies on SMAC mimetics.